POSACONAZOLE
Generic: POSACONAZOLE
Basic Information
Manufacturer
Camber Pharmaceuticals, Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
INTRAVENOUS
FDA Set ID
c551e121-d5fc-4b35-ba9f-72ce3a314fdc
Indications & Usage
1 INDICATIONS AND USAGE Posaconazole is an azole antifungal indicated as follows: • Posaconazole is indicated for the prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy as follows: ( 1.2 ) o Posaconazole injection : adults and pediatric patients 2 years of age and older 1.2 Prophylaxis of Invasive Aspergillus and Candida Infections Posaconazole is indicated for the prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy [see Clinical Studies ( 14.1 )] as follows: • Posaconazole injection: adults and pediatric patients 2 years of age and older.
Adverse Reactions
6 ADVERSE REACTIONS The following serious and otherwise important adverse reactions are discussed in detail in another section of the labeling: • Hypersensitivity [see Contraindications (4.1) ] • Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2) ] • Hepatic Toxicity [see Warnings and Precautions (5.5) ] • Adult Patients: Common adverse reactions in studies with posaconazole in adults are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia.
( 6.1 ) • Pediatric Patients: Common adverse reactions (incidence >20% receiving 6 mg/kg posaconazole injection in a study in pediatric patients are pyrexia, febrile neutropenia, vomiting, mucosal inflammation, pruritus, hypertension, hypokalemia, and stomatitis.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aspiro Pharma Limited at 1-866-495-1995, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of posaconazole cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clinical Trial Experience in Adults Clinical Trial Experience with Posaconazole Injection for Prophylaxis Multiple doses of posaconazole injection administered via a peripheral venous catheter were associated with thrombophlebitis (60% incidence).
Therefore, in subsequent studies, posaconazole injection was administered via central venous catheter.
The safety of posaconazole injection has been assessed in 268 patients in a clinical trial.
Patients were enrolled in a non-comparative pharmacokinetic and safety trial of posaconazole injection when given as antifungal prophylaxis (Posaconazole Injection Study).
Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT.
This patient population was 55% male, had a mean age of 51 years (range 18 to 82 years, 19% of patients were ≥65 years of age), and were 95% white and 8% Hispanic.
Ten patients received a single dose of 200 mg posaconazole injection, 21 patients received 200 mg daily dose for a median of 14 days, and 237 patients received 300 mg daily dose for a median of 9 days.
Table 8 presents adverse reactions observed in patients treated with posaconazole injection 300 mg daily dose in the posaconazole Injection Study.
Each patient received a loading dose, 300 mg twice on Day 1.
Following posaconazole intravenous therapy, patients received Noxafil oral suspension to complete 28 days of total posaconazole therapy.
Table 8: Posaconazole Injection Study: Adverse Reactions in at Least 10% of Subjects Treated with Posaconazole Injection 300 mg Daily Dose Body System Posaconazole Injection Treatment Phase n=237 (%) * Posaconazole Injection Treatment Phase or Subsequent Noxafil Oral Suspension Treatment Phase n=237 (%) † Subjects Reporting any Adverse Reaction 220 (93) 235 (99) Blood and Lymphatic System Disorder Anemia 16 (7) 23 (10) Thrombocytopenia 17 (7) 25 (11) Gastrointestinal Disorders Abdominal Pain Upper 15 (6) 25 (11) Abdominal Pain 30 (13) 41 (17) Constipation 18 (8) 31 (13) Diarrhea 75 (32) 93 (39) Nausea 46 (19) 70 (30) Vomiting 29 (12) 45 (19) General Disorders and Administration Site Conditions Fatigue 19 (8) 24 (10) Chills 28 (12) 38 (16) Edema Peripheral 28 (12) 35 (15) Pyrexia 49 (21) 73 (31) Metabolism and Nutrition Disorders Decreased appetite 23 (10) 29 (12) Hypokalemia 51 (22) 67 (28) Hypomagnesemia 25 (11) 30 (13) Nervous System Disorders Headache 33 (14) 49 (21) Respiratory, Thoracic and Mediastinal Disorders Cough 21 (9) 31 (13) Dyspnea 16 (7) 24 (10) Epistaxis 34 (14) 40 (17) Skin and Subcutaneous Tissue Disorders Petechiae 20 (8) 24 (10) Rash 35 (15) 56 (24) Vascular Disorders Hypertension 20 (8) 26 (11) *Adverse reactions reported in patients with an onset during the posaconazole intravenous dosing phase of the study.
† Adverse reactions reported with an onset at any time during the study in patients who were treated for up to 28 days of posaconazole therapy.
The most frequently reported adverse reactions with an onset during the posaconazole intravenous phase of dosing with 300 mg once daily were diarrhea (32%), hypokalemia (22%), pyrexia (21%), and nausea (19%).
These adverse reactions were consistent with those seen in studies with Noxafil oral suspension.
Other clinically significant adverse reactions reported in less than 5% of patients in clinical trials of posaconazole are listed below: • Blood and lymphatic system disorders: hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, neutropenia aggravated • Endocrine disorders: adrenal insufficiency • Nervous system disorders: paresthesia • Immune system disorders: allergic reaction [see Contraindications (4.1) ] • Cardiac disorders: torsades de pointes [see Warnings and Precautions (5.2) ] • Vascular disorders: pulmonary embolism • Gastrointestinal disorders: pancreatitis • Liver and Biliary System Disorders: hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundice • Renal & Urinary System Disorders: renal failure acute Clinical Trial Experience in Pediatrics Clinical Trial Experience in Pediatric Patients (2 to less than 18 Years of Age) The safety of posaconazole injection and Noxafil PowderMix for delayed-release oral suspension for prophylaxis of invasive fungal infections has been assessed in an open label uncontrolled dose-ranging PK and safety study (Posaconazole injection/ Noxafil PowderMix for delayed-release oral suspension Pediatric Study 1, NCT02452034); hereinafter referred to as Posaconazole Pediatric Study) in 115 immunocompromised pediatric patients 2 to less than 18 years of age with known or expected neutropenia.
Posaconazole injection and Noxafil PowderMix for delayed-release oral suspension was administered at daily doses of up to 6 mg/kg (twice daily on day 1) in three dose cohorts.
All 115 subjects initially received posaconazole injection for at least 7 days, and 63 subjects were transitioned to Noxafil PowderMix for delayed-release oral suspension.
The mean overall treatment duration for all treated subjects was 20.6 days with 14.3 days (range: 1 to 28 days) on posaconazole injection and 11.6 days (range: 2 to 18 days) on Noxafil PowderMix for delayed-release oral suspension [see Clinical Pharmacology (12.3) ].
Table 15 presents adverse reactions observed in greater than or equal to 10% of pediatric patients treated with posaconazole in the Posaconazole Pediatric Study.
Reported adverse reaction profile of posaconazole in pediatric patients was consistent with the safety profile of posaconazole in adults.
The most common adverse reactions (occurring in greater than 20% of pediatric patients receiving 6 mg/kg posaconazole injection and Noxafil PowderMix for delayed-release oral suspension daily dose) were pyrexia, febrile neutropenia, vomiting, mucosal inflammation, pruritus, hypertension, hypokalemia, and stomatitis.
Table 15: Adverse Reactions in at Least 10% of Pediatric Patients Treated with Posaconazole Injection and Noxafil PowderMix for Delayed-Release Oral Suspension Adverse Reaction Posaconazole Injection and Noxafil PowderMix for Delayed-Release Oral Suspension 6 mg/kg Dose Cohort n=49 (%) Posaconazole Injection and Noxafil PowderMix for Delayed-Release Oral Suspension All Dose Cohorts n=115 (%) Pyrexia 16 (33) 50 (43) Febrile neutropenia 15 (31) 25 (22) Vomiting 12 (24) 30 (26) Mucosal inflammation 11 (22) 32 (28) Pruritus 11 (22) 18 (16) Hypertension 10 (20) 20 (17) Hypokalemia 10 (20) 16 (14) Stomatitis 10 (20) 13 (11) Diarrhea 9 (18) 25 (22) Nausea 9 (18) 18 (16) Abdominal pain 8 (16) 20 (17) Decreased appetite 7 (14) 17 (15) Rash 7 (14) 18 (16) Alanine aminotransferase increased 6 (12) 8 (7) Headache 6 (12) 16 (14) Aspartate aminotransferase increased 5 (10) 8 (7) The number of patients receiving posaconazole in the Posaconazole Pediatric Study who had changes in liver tests from Grade 0, 1, or 2 at baseline to Grade 3 or 4 is presented in Table 16 .
Table 16: Posaconazole Pediatric Study: Changes in Liver Tests from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 Number (%) of Patients with Change* Pediatric Study 1 Laboratory Parameter Posaconazole Injection and Noxafil PowderMix for Delayed-Release Oral Suspension (6 mg/kg daily) n=49 (%) AST 2/49 (4) ALT 3/49 (6) Bilirubin 0/48 (0) Alkaline Phosphatase 0/48 (0) * Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study.
These data are presented in the form X/Y, where X represents the number of patients who met the criterion as indicated, and Y represents the number of patients who had a baseline observation and at least one post-baseline observation.
CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase; ALT= Alanine Aminotransferase 6.2 Postmarketing Experience The following adverse reaction has been identified during the post-approval use of posaconazole.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.
Endocrine Disorders: Pseudoaldosteronism
( 6.1 ) • Pediatric Patients: Common adverse reactions (incidence >20% receiving 6 mg/kg posaconazole injection in a study in pediatric patients are pyrexia, febrile neutropenia, vomiting, mucosal inflammation, pruritus, hypertension, hypokalemia, and stomatitis.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aspiro Pharma Limited at 1-866-495-1995, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of posaconazole cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clinical Trial Experience in Adults Clinical Trial Experience with Posaconazole Injection for Prophylaxis Multiple doses of posaconazole injection administered via a peripheral venous catheter were associated with thrombophlebitis (60% incidence).
Therefore, in subsequent studies, posaconazole injection was administered via central venous catheter.
The safety of posaconazole injection has been assessed in 268 patients in a clinical trial.
Patients were enrolled in a non-comparative pharmacokinetic and safety trial of posaconazole injection when given as antifungal prophylaxis (Posaconazole Injection Study).
Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT.
This patient population was 55% male, had a mean age of 51 years (range 18 to 82 years, 19% of patients were ≥65 years of age), and were 95% white and 8% Hispanic.
Ten patients received a single dose of 200 mg posaconazole injection, 21 patients received 200 mg daily dose for a median of 14 days, and 237 patients received 300 mg daily dose for a median of 9 days.
Table 8 presents adverse reactions observed in patients treated with posaconazole injection 300 mg daily dose in the posaconazole Injection Study.
Each patient received a loading dose, 300 mg twice on Day 1.
Following posaconazole intravenous therapy, patients received Noxafil oral suspension to complete 28 days of total posaconazole therapy.
Table 8: Posaconazole Injection Study: Adverse Reactions in at Least 10% of Subjects Treated with Posaconazole Injection 300 mg Daily Dose Body System Posaconazole Injection Treatment Phase n=237 (%) * Posaconazole Injection Treatment Phase or Subsequent Noxafil Oral Suspension Treatment Phase n=237 (%) † Subjects Reporting any Adverse Reaction 220 (93) 235 (99) Blood and Lymphatic System Disorder Anemia 16 (7) 23 (10) Thrombocytopenia 17 (7) 25 (11) Gastrointestinal Disorders Abdominal Pain Upper 15 (6) 25 (11) Abdominal Pain 30 (13) 41 (17) Constipation 18 (8) 31 (13) Diarrhea 75 (32) 93 (39) Nausea 46 (19) 70 (30) Vomiting 29 (12) 45 (19) General Disorders and Administration Site Conditions Fatigue 19 (8) 24 (10) Chills 28 (12) 38 (16) Edema Peripheral 28 (12) 35 (15) Pyrexia 49 (21) 73 (31) Metabolism and Nutrition Disorders Decreased appetite 23 (10) 29 (12) Hypokalemia 51 (22) 67 (28) Hypomagnesemia 25 (11) 30 (13) Nervous System Disorders Headache 33 (14) 49 (21) Respiratory, Thoracic and Mediastinal Disorders Cough 21 (9) 31 (13) Dyspnea 16 (7) 24 (10) Epistaxis 34 (14) 40 (17) Skin and Subcutaneous Tissue Disorders Petechiae 20 (8) 24 (10) Rash 35 (15) 56 (24) Vascular Disorders Hypertension 20 (8) 26 (11) *Adverse reactions reported in patients with an onset during the posaconazole intravenous dosing phase of the study.
† Adverse reactions reported with an onset at any time during the study in patients who were treated for up to 28 days of posaconazole therapy.
The most frequently reported adverse reactions with an onset during the posaconazole intravenous phase of dosing with 300 mg once daily were diarrhea (32%), hypokalemia (22%), pyrexia (21%), and nausea (19%).
These adverse reactions were consistent with those seen in studies with Noxafil oral suspension.
Other clinically significant adverse reactions reported in less than 5% of patients in clinical trials of posaconazole are listed below: • Blood and lymphatic system disorders: hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, neutropenia aggravated • Endocrine disorders: adrenal insufficiency • Nervous system disorders: paresthesia • Immune system disorders: allergic reaction [see Contraindications (4.1) ] • Cardiac disorders: torsades de pointes [see Warnings and Precautions (5.2) ] • Vascular disorders: pulmonary embolism • Gastrointestinal disorders: pancreatitis • Liver and Biliary System Disorders: hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundice • Renal & Urinary System Disorders: renal failure acute Clinical Trial Experience in Pediatrics Clinical Trial Experience in Pediatric Patients (2 to less than 18 Years of Age) The safety of posaconazole injection and Noxafil PowderMix for delayed-release oral suspension for prophylaxis of invasive fungal infections has been assessed in an open label uncontrolled dose-ranging PK and safety study (Posaconazole injection/ Noxafil PowderMix for delayed-release oral suspension Pediatric Study 1, NCT02452034); hereinafter referred to as Posaconazole Pediatric Study) in 115 immunocompromised pediatric patients 2 to less than 18 years of age with known or expected neutropenia.
Posaconazole injection and Noxafil PowderMix for delayed-release oral suspension was administered at daily doses of up to 6 mg/kg (twice daily on day 1) in three dose cohorts.
All 115 subjects initially received posaconazole injection for at least 7 days, and 63 subjects were transitioned to Noxafil PowderMix for delayed-release oral suspension.
The mean overall treatment duration for all treated subjects was 20.6 days with 14.3 days (range: 1 to 28 days) on posaconazole injection and 11.6 days (range: 2 to 18 days) on Noxafil PowderMix for delayed-release oral suspension [see Clinical Pharmacology (12.3) ].
Table 15 presents adverse reactions observed in greater than or equal to 10% of pediatric patients treated with posaconazole in the Posaconazole Pediatric Study.
Reported adverse reaction profile of posaconazole in pediatric patients was consistent with the safety profile of posaconazole in adults.
The most common adverse reactions (occurring in greater than 20% of pediatric patients receiving 6 mg/kg posaconazole injection and Noxafil PowderMix for delayed-release oral suspension daily dose) were pyrexia, febrile neutropenia, vomiting, mucosal inflammation, pruritus, hypertension, hypokalemia, and stomatitis.
Table 15: Adverse Reactions in at Least 10% of Pediatric Patients Treated with Posaconazole Injection and Noxafil PowderMix for Delayed-Release Oral Suspension Adverse Reaction Posaconazole Injection and Noxafil PowderMix for Delayed-Release Oral Suspension 6 mg/kg Dose Cohort n=49 (%) Posaconazole Injection and Noxafil PowderMix for Delayed-Release Oral Suspension All Dose Cohorts n=115 (%) Pyrexia 16 (33) 50 (43) Febrile neutropenia 15 (31) 25 (22) Vomiting 12 (24) 30 (26) Mucosal inflammation 11 (22) 32 (28) Pruritus 11 (22) 18 (16) Hypertension 10 (20) 20 (17) Hypokalemia 10 (20) 16 (14) Stomatitis 10 (20) 13 (11) Diarrhea 9 (18) 25 (22) Nausea 9 (18) 18 (16) Abdominal pain 8 (16) 20 (17) Decreased appetite 7 (14) 17 (15) Rash 7 (14) 18 (16) Alanine aminotransferase increased 6 (12) 8 (7) Headache 6 (12) 16 (14) Aspartate aminotransferase increased 5 (10) 8 (7) The number of patients receiving posaconazole in the Posaconazole Pediatric Study who had changes in liver tests from Grade 0, 1, or 2 at baseline to Grade 3 or 4 is presented in Table 16 .
Table 16: Posaconazole Pediatric Study: Changes in Liver Tests from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 Number (%) of Patients with Change* Pediatric Study 1 Laboratory Parameter Posaconazole Injection and Noxafil PowderMix for Delayed-Release Oral Suspension (6 mg/kg daily) n=49 (%) AST 2/49 (4) ALT 3/49 (6) Bilirubin 0/48 (0) Alkaline Phosphatase 0/48 (0) * Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study.
These data are presented in the form X/Y, where X represents the number of patients who met the criterion as indicated, and Y represents the number of patients who had a baseline observation and at least one post-baseline observation.
CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase; ALT= Alanine Aminotransferase 6.2 Postmarketing Experience The following adverse reaction has been identified during the post-approval use of posaconazole.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.
Endocrine Disorders: Pseudoaldosteronism